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Publication numberUS3423507 A
Publication typeGrant
Publication dateJan 21, 1969
Filing dateFeb 25, 1966
Priority dateFeb 25, 1966
Publication numberUS 3423507 A, US 3423507A, US-A-3423507, US3423507 A, US3423507A
InventorsRudolph Neri
Original AssigneeSchering Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method of treating benign prostratic hypertrophy
US 3423507 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions comprising as the essential active ingredient 1a,2a-II1CihylI16-6-Ch1OI0l7a-1OWEI alkanoyloxy-G-dehydroprogesterone are useful in the treatment of benign prostatic hypertrophy. Preferred are compositions comprising 1u,2a-methylene'6-chloro-17aacetoxy-o-dehydroprogesterone.

This invention relates to new therapeutic formulations useful in the control and treatment of benign prostatic hypertrophy and to the process of treating benign prosatic hypertrophy which comprises the administration of dosage units of such therapeutic formulations.

Benign prostatic hypertrophy occurs spontaneously in man as well as dogs. In both species, the frequency of the hypertrophic condition seems to increase with increasing ;:age. In the United States, it has been estimated that more than one-half of the male population over fifty years of age is afflicted with benign prostatic tumors and that the ncidence approaches 70 to 90 percent as age increases. 1 us benign prostatic hypertrophy presents a major problem for which there has heretofore existed no satisfactory treatment other than surgery.

At the present time, the etiological and pathogenic factors which lead to the hypertrophic condition in dogs and in man are considered by many investigators to be identical. Although numerous theories have been advanced on the etiology of benign prostatic hypertrophy, none have been fully accepted and none have aided in the identification of the true etiology of the problem since the preventive or therapeutic measures heretofore suggested in these theories have failed. For example, most investigators in the field presently believe that benign prostatic hyper trophy results from an imbalance of androgenic and estrogenic hormones, although prostatic growth appears to be androgen-dependent. Hormone therapy (i.e. administration of estrogens such as stilbesterol), however, has not proved to be fully etficacious in providing meaningful remissions and cures, the condition frequently recurring following cessation of estrogen therapy.

Surgical ablation, although an effective therapy for benign pros-tatic hypertrophy, is not entirely satisfactory since severe complications may arise. In addition to a mortality rate of 2 to 3 percent which may be anticipated in patients subjected to transurethral prostatectomy, many patients experience some nonfatal complications such as epididymitis, pneumonia, pyelonephritis, secondary resection, etc. The need for another and effective form of therapy. therefore, is clear.

The instant invention is based upon applicants discovery that administration of dosage units of therapeutic formulations containing a 17a-lower alkanoyl ester of 1a,20t methylene 6 chloro 6 dehydro 17a hydroxy-progesterone produces a marked reduction in the hypertrophic prostate. Further, and surprisingly, administration of these esters in dosages sufiicient to achieve the anti-hypertrophic response is unaccompanied by objectional side effects, 'epsecially the suppression of adrenal function often displayed by progrestational hormones.

The anti-hypertrophic effect of these compounds has been confirmed by actual in vivo evaluation in dogs employing standard pharmacological techniques. Thus, the instant invention constitutes an important advance in the treatment of benign prostatic hypertrophy.

In its composition aspect, therefore, the instant invention is described as residing in the concept of therapeutic formations for the treatment and control of benign prostatic hypertrophy containing as the essential active ingredient 101,20: methylene 6 chloro 6- dehydro 17a hydroxy-progesterone esteriified at the l7-position with a lower alkanoic acid group.

In its process aspect, the instant invention may be described as residing in the concept of the method for the treatment and control of benign prostatic hypertrophy which comprises administering -dosage units of a therapeutic formulation containing as the essential active ingredient 10:,204 methylene 6 chloro 6 dehydro -17cc hydroxy-progesterone having at the 17-position a lower alkanoyloxy group.

As used herein, the term, lower alkanoic acid is in tended to include hydrocarbon carboxylic acids, including straight and branched chain acids, having from 1 to 8 carbon atoms. Included in this group are, for example, but without limiting the generality of the foregoing, acetic acid, propionic acid, butyric acid, Mnethylpropionic acid, valeric acid, hexanoic acid and the like. Acetic acid esters are particularly preferred.

The active esters of this invention are either well-known compounds (see, for example, South Africa Patent 62/ 1,250, filed Mar. 26, 1962) or may be readily prepared by methods conventional in the art of which the following procedure is typical:

A 1a,2a-methylene-6-dehydro-l7a-hydroxy progesterone l7-ester, such as the acetate, is converted into the corresponding 6a,7a-epoxide 'by the action of a percar- 'boxylic acid, such as perbenzoic acid, in a suitable solvent, such as ethylene chloride. The reaction mixture is kept for 12 to 20 hours at about 5 C. and for an additional 5 to 10 hours at about room temperature. It is then diluted, with methylene chloride for example, and Washed with aqueous ferrous sulfate solution, sodium bicarbonate solution and with water until neutral. The organic phase is separated and evaporated to dryness. The resulting crude 6a,7u-epoxide, preferably in glacial acetic acid, is then saturated with gaseous hydrogen chloride at room temperature for 18 to 24 hours whereby, in one operation, the cyclopropane ring is opened with the formation of a lwchloro-methyl group and the epoxy ring is opened with the splitting off of water and the formation of the 6-chloro-6-dehydro grouping. The crude product, after the reaction mixture has been diluted with methylene chloride, washed neutral with water and dried over sodium sulfate, is recovered by separating the organic phase and evaporating to dryness. The lulu-methylene group is then regenerated by refluxing the crude product under a nitrogen atmosphere for about 30 minutes with an organic base such as collidine. The reaction mixture is diluted with ether, washed with about 4 N hydrochloric acid, and then washed with water until neutral. The crude residue remaining after drying the reaction mixture over sodium sulphate and evaporating the organic phase to dryness is chromatographed over silica gel preferably with a benzene-ethyl acetate mixture (19:1). Recovery of the eluted product and recrystallization from an organic solvent, such as isoprbpyl ether, yields the pure 1a,2a-methylene-6-chloro-6-dehydro-17ahydroxy-progesterone 17-ester (i.e. the acetate in the sequence above).

The active esters of this invention can 'be administered orally in the form of tablets, capsules, elixirs and the like or may be administered by parenteral injection. In tablet form they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, gums, starches, and sugars. They may also be incorporated into gelatin capsules or formulated into elixirs which have the advantage of being susceptible to manipulations in flavor :by the addition of standard natural or synthetic flavoring agents. Highly satisfactory administration may also be achieved in the form of aqueous parenteral suspensions. Preferably, these formulations are so proportioned as to afford a unit dosage of from about 1 to about 100 mg. of active ester. Particularly preferred are unit dosages ranging from about 5 to about 25 mg.

Typical formulations incorporating the active esters of this invention are described below. These formulations are intended to be illustrative merely and no limitation is implied or intended except as set forth in the appended claims.

Tablet formulations Formula A (5 mg): Milligrams per tabii 1a,2a-methylene-6-chl0ro 6 dehydro 17a- Lactose, USP (spray dried) 164.0 Magnesium stearate, USP 1.0

Pass the steroid through a high speed mill equipped with a 100 to 150 mesh screen. Blend the milled steroid with the starch in a suitable mixing vessel. Add an equal weight of the spray dried lactose to the blend and mix until uniform. Combine the resultant blend with the remainder of the spray dried lactose and mix until uniform. Charge the magnesium stearate with a portion of the active tablet mix and blend. Blend the magnesium stearate mix with the remaining active tablet base. Continue mixing until uniform. Compress to target weight (100.0 mg. for 5 mg. tablet and 200.0 mg. for 25 mg. tablet).

Capsule formulation Formula: Milligrams per capsule lu,2ot-met'hylene-6-chloro 6 dehydro 17ahydroxy-progesterone valerate 5.0 Lactose, USP (spray dried) 292.0 Magnesium stearate, USP 3.0

Blend ingredients until uniformly mixed. Fill into hard gelatin capsule.

Parenteral suspension Formula A (5 mg): Milligrams per milliliter 1a,2a-met hylene-6-chloro 6 dehydro 17a- Propylparaben, USP 0.20 Water for injection, USP, q.s. ad 1.00

Charge 45 l. of water for injection into a suitable stainless steel vessel and heat to 90 C. With vigorous agita tion, slowly sprinkle the methyl cellulose into the hot Water (5 gm. for Formula A or 25 gm. for Formula B).i Agitate until the methyl cellulose is "thoroughly dispersed and wetted. Add approximately 30 l. of cold (05 C.),i water for injection. Cool the entire mixture to 8 C. Dissolve the sodium citrate (600 gm. for Formula A or 3000 gm. for Formula B) in enough water for injection to make 5 l. of solution. Slowly and with agitation add this solution to the cooled methyl cellulose solutionf Dissolve the parabens (180 gm. of methyl and 20 gm. of propyl) in g 900 gm. of benzyl alcohol which has been heated to 30; C. Charge this solution to the chilled methyl cellulose solution. Bring the resulting solution to l. with water "for injection and agitate until uniform. In a sterile area,

pass the batch through a sterile filter. Aseptically transferl about 3.5 l. of the sterile methyl cellulose solution to a,

separate container reserving the remainder of the batch, in a sterile stainless steel mixing tank. Slurry the steroid in a sterile colloid mill with about 2 l. of the separated methyl cellulose solution and add the slurry to the solu-; tion in the mixing tank. Rinse the slurry container and thel mill with the remaining 1.5 l. of reserved methyl cellulose, solution and add the rinse to the mixing tank. Rinse the slurry container and mill with 2 l. of water for injection and add the rinse to the mixing tank. Adjust the volume in the mixing tank to l. with water for injection and agitate until uniform. The batch affords 100 l. of sterile suspension having the proportions of Formula A or Formula B.

In order to achieve a satisfactory response in the treatment and control of benign prostatic hypertrophy, it is usually necessary to administer daily 1 to 4 tablets or capsules :as described above. The usual injjection dosage is 1 to 4 ml. per day. In severe or aggravated conditions, additional medication may be administered.

Although the invention has been described above in terms of 17ix-lower alkanoyl esters of 1a,2a-methylene-6 chloro-6-dehydro-17othydroxy-progesterone as the essential active ingredient, many modifications in these compositions of matter will suggest themselves to one skilled in the :art from the foregoing disclosure. It will be obvious, for example, that the chlorine atom at the 6-position may be replaced by other substituents such as a fluoro or a methyl group. It will also be obvious that a lower alkylene group such as methylene may be present at position 16.

The nature of the vehicle employed is not an essential part of this invention. Various modifications in therapeutic formulation Will suggest themselves to one skilled in the art.

The subject matter which applicant regards as his in vention is particularly pointed out and distinctly claimed 5. The method of claim 1 wherein the lower alkanoic as follows: acid group is caproate.

1. The method of treating benign prostatic hypertrophy in an animal having a hypertrophic prostate which comf r nces Clted arises the iFternall tadministration of glosage utnitls otfi 2 5 UNITED STATES PATENTS erapeu 1c orrnu a 1011 comprising as e essen 1a ac v ingredient from about 1 to about 100 mgm. of 1u,2a- 3234093 2/1966 Wlechert I 5 methylene6-chloro-17a-hydroxy 6-dehydroprogesterone 3338893 8/1967 Beard et a 260 esterified at the 17-position with a lower alk anoic acid OTHER REFERENCES group, whereby said hypertrophic prostate is reduced.

2. The method of claim 1 wherein the lower alkanoic acid group is acetate.

3. The ITICtl'lOCl Of claim 1 wherein the lOWCI alkanoic FRANK CACCIAPAGLIA JR" Primary Exmnineh acid group is propionate.

4. The method of claim 1 wherein the lower alkanoic 15 US 1. acid group is valerate. 239 55, 3974 10 The Merk Manual, eighth ed., 1950, pp. 589592.

Index Medicus, 8:3, March 1967, p. 355.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3234093 *Apr 24, 1962Feb 8, 1966Schering Ag6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions
US3338893 *Oct 22, 1965Aug 29, 1967Syntex CorpFused halocyclopropyl steroids
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3937700 *Jul 18, 1973Feb 10, 1976U.S. Philips CorporationNovel 1,2-methylene-17α-acyloxy (or improved hydroxy)-9β, 10α-steroid compounds of the pregnane series, pharmaceutic preparations on the basis of the novel compounds and methods of producing said compounds and preparations
US4310523 *Oct 10, 1980Jan 12, 1982Schering AktiengesellschaftCombined antiestrogens and antigonadotropically effective antiandrogens for the prophylaxis and therapy of hyperplasia of the prostate
US4596797 *May 13, 1985Jun 24, 1986Schering AktiengesellschaftUse of aromatase-inhibitors for prophylaxis and/or treatment of benign prostatic hyperplasia
US4598072 *Dec 10, 1982Jul 1, 1986Schering AktiengesellschaftCombinations of an aromatase-inhibitor and an antiandrogen for prophylaxis and/or treatment of benign prostatic hyperplasia
US5382434 *Mar 22, 1994Jan 17, 1995Akzo N.V.Low steroid dose dry pharmaceutical preparation
US20070078091 *Sep 8, 2006Apr 5, 2007Doris HublerPharmaceutical combinations for compensating for a testosterone deficiency in men while simultaneously protecting the prostate
DE3339295A1 *Oct 27, 1983May 17, 1984Schering Ag4-Hydroxy- and 4-acyloxy-4-androstene-3,17-diones for use in the prophylaxis and therapy of prostate hyperplasia and compositions containing these for such a use
U.S. Classification514/178, 540/81, 552/511
Cooperative ClassificationA61K31/565